The involvement of the nervous system in direct and indirect regulation of the immune response is now well recognized, however, the mechanisms of these interactions remain unknown. It has been demonstrated that neuropeptides play a role in lymphocyte function and in inflammation. Attempts to understand mechanisms that result in intraocular inflammation have not adequately explained many clinical uveitis entities. Experimental and clinical evidence suggests a role for neural damage and for neuropeptides in some forms of inflammatory ocular disease. The purpose of the investigation is to study the neural-immune interactions in leprosy and to apply this information to other forms of intraocular inflammation and peripheral neuropathies. Mycobacterium leprae infection was chosen since leprosy is a leading cause of blindness and a major peripheral nerve disorder. A major cause of blindness in leprosy is chronic uveitis. In this proposal, the relationship between the neural infection with M. leprae neuropeptide release, and uveitis will be studied by localization of neuropeptides in normal and M. leprae infected uveal tissues, and by testing the effect of neuropeptides on uveal inflammation following intravitreal and other routes of delivery. An in vitro model system will be established to study the interaction between M. leprae and cultured neurons. This system will be further modified to assess the role of neuropeptide expression on the intracellular viability of M. leprae. In addition, exposure of cultured neurons to both naive and activated immune cells will indicate if the neuron can express surface antigens which would serve as targets for immune cells. Immunochemical probes for MHC class II antigens and the major classes of T-lymphocytes will be used in is work. The possibility of direct involvement of the axons of the sensory nerves of the anterior segment will be studied by this in vitro system. Other experiments will be designed to study the mechanism of interaction between M. leprae and cells in the anterior segment of the eye. The unique ultrastructural and immunological properties of the cornea will be exploited in order to gain an understanding of the development of the local and systemic immune responses to M. leprae antigens. In general, this research should lend insight to understanding other peripheral neuropathies such as those accompanying herpetic infections and diabetes. Further, new mechanisms such as neuropeptide release and localization will be examined as a cause of intraocular inflammation, uveitis, a leading cause of blindness in our society.